The hepatitis C virus (HCV) is a positive strand RNA virus of the Flavivirus family that infects hepatocytes of humans and some other primates. First characterized in 1989 (1), HCV has a 9.5 kb genome that encodes for three structural proteins: core and two envelope glycoproteins (E1 and E2), as well as several non-structural (NS) proteins that are involved in the viral replication and interaction with the host cell (2).
HCV is a serious public health concern, causing >90% of parenteral non-A, non-B hepatitis (1). From 0.4 to 1.5% of the world's population is infected (3, 4), including about 300,000 Canadians (Health Canada). Epidemiological statistics are difficult to compile since the vast majority of acute infections are subclinical; however it is estimated that 50-80% of HCV infected individuals fail to clear the virus, and most of these become life-long carriers. About 50% of carriers develop chronic hepatitis and 20% of these will develop liver cirrhosis, many of whom will subsequently develop hepatocellular carcinoma (5-9). Hepatitis C causes an estimated 8,000 to 10,000 deaths annually in the United States (CDC).
In the United States and Canada, there are two different regimens, which have been approved as therapy for hepatitis C: monotherapy with alpha interferon and combination therapy with alpha interferon and Ribavirin. Although more expensive and associated with more side effects, combination therapy consistently yields higher rates of sustained response than monotherapy.
Several forms of alpha interferon are available (alpha-2a, alpha-2b, and consensus interferon (Alfacon)). These interferons are typically given subcutaneously three times weekly. Pegylated interferon, i.e., alpha interferon modified by addition of polyethylene glycol (PEG) in order to increase the duration in the circulation, is another of interferon, and it is given only once weekly. Ribavirin, in contrast, is an oral antiviral agent that is given twice a day in 200 mg capsules.
Side effects of alpha interferon include: fatigue, muscle aches, headaches, nausea and vomiting, skin irritation at the injection site, low-grade fever, weight loss, irritability, depression, suicide, mild bone marrow suppression and hair loss (reversible). For Ribavirin the side effects include; anemia fatigue and irritability, itching, skin rash, nasal stuffiness, sinusitis and cough.
Treatment with interferon alone or in combination with interferon and Ribavirin leads to rapid improvements in serum ALT levels in 50-75% of patients and the disappearance of detectable HCV RNA from the serum in 30-50% of patients. Long-term improvement in liver disease usually occurs only if HCV RNA disappears during therapy and stays undetectable for at least 6 months after therapy is completed. Combination treatment results in both a higher rate of loss of HCV RNA on treatment and a lower rate of relapse when treatment is complete. However, results depend strongly on the genotype of virus, with better results being obtained for genotypes 2 and 3 (about 90% with 1 year of treatment with pegylated IFN-α and Ribavirin), but much poorer results (about 40% sustained response) for genotype 1 HCV. The majority of HCV chronic carriers in North America now are of genotype 1.
The optimal duration of treatment varies depending on whether interferon monotherapy or combination therapy is used, as well as by HCV genotype. Typically, the duration ranges from 6 to 12 months.
There is currently no vaccine against HCV, or highly effective therapy for chronic infection. Thus there is an urgent need for an effective treatment that could be used to treat chronic carriers.